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Enabling motor control after a spinal cord injury through nanoscaled electrical

Periodic Reporting for period 2 - EPI_nanoSTIM (Enabling motor control after a spinal cord injury through nanoscaled electrical)

Période du rapport: 2017-10-01 au 2018-09-30

A spinal cord injury causes motor paralysis, sensory deficit, autonomic dysfunctions and a series of life-threatening complications that can now rarely be ameliorated. In case of a complete paralysis, the chances of recovering volitional motor control below injury after two years is negligible.
Electrical stimulation of the spinal cord has been recently used to elicit volitional motor control in paraplegics, although no detailed analysis has ever been performed to define the optimal characteristics to facilitate recovery. Indeed, only stereotyped trains of pulses are still employed in experimental research and clinics, and yield to highly variable functional outcomes, possibly associated with debilitating side effects due to the high intensity used.
Moreover, current electrostimulators do not allow the safe delivery of customized signals and the possibility to simultaneously stimulate and record epidural potentials to target stimulation over the most effective sites.
This study tested on preclinical models some promising innovative hardware and software tools to suggest promising clinical trials to improve volitional motor recovery after spinal cord injury.
The main aims of the project were to:
- refine a multielectrode array interface recently designed at UCLA, exploring new materials;
- use the array to stimulate and record electrical potentials from the surface of the dorsal cord;
- find the most responsive sites to stimulation and assess the functionality of spinal tracts pre- and post- lesion;
- develop and identify new variable patterns of stimulation to restore descending motor control after spinal cord injury;
- explore the mechanisms supporting this innovative neuromodulation.
The project clearly indicated that a variable protocol of stimulation, called Dynamic Stimulation (DS), potentiates the motor output in rats with and without a spinal cord injury. Furthermore, the innovative epidural multielectrode arrays used in the current project are optimal to selectively activate distinct spinal and cortical areas. Finally, I validated the new interface for recording electrical potentials from the surface of the dorsal cord.
The project began with the acquisition of all certifications and licenses for performing preclinical studies and the training on in vivo spinal cord research. This was accompanied by an extensive study of literature in the field, which led to a fundamental review paper about the neurophysiological mechanisms of spinal neuromodulation.
Then, I used terminal experiments to design new protocols of electrical stimulation and evaluate the impact of acute stimulation in modulating and restoring spinally-induced motor responses from the rat hind limbs. I delivered this complex pattern through a multi-electrode planar epidural array recently devised at UCLA, which was further improved using new materials and coatings to maximize fidelity of charge transfer.
Then, DS was continuously delivered to multiple segments of the spinal cord, at very low intensity and with opposite cathode/anode location, to assess DS efficacy and compare it to standard trains of stereotyped pulses currently used in experimental research and clinics. In fully-anesthetized neurologically-intact animals, DS modulated the amplitude of motor responses, increased spinal network excitability and potentiated weak input from the brain to the cord. Moreover, acute supply of DS to spinally injured rats restored considerable hindlimb activity. DS was then delivered to animals with a chronic spinal cord injury to explore the intrinsic mechanisms of motor output modulation by spinal neuronal circuits and the pathophysiology of an acute spinal cord injury.
DS proved as a reliable first strategy to limit the loss of functions following a spinal cord injury, opening a new vision about the early management of spinal cord injuries.

In addition, DS facilitated cortico-spinal connectivity and, when associated with locomotor training, it promoted plastic rearrangements of interneuronal networks in animals with a spinal injury.
The new interface also allowed recordings of electrical potentials from the surface of the cord during peripheral nerve stimulation, demonstrating the selectivity of each independent electrode of the array in detecting neuronal activity and thus identify the best sites to act upon to optimize stimulation for neurorehabilitation.

The results led to one published review, three manuscripts that are deemed to be published during this year, various seminars and presentations in world-class conferences, as well as an international network of collaborations with world-class laboratories to nourish promising research and scientific multicenter studies. Finally, the important advancements obtained in spinal cord research have high potentials of being proposed soon to clinical researchers.
The project mainly created DS, which is more effective than current stimulating protocols in facilitating motor control, by recruiting a wider propriospinal network and increasing spinal excitability to evoke larger muscle responses.
Moreover, the acute supply of DS across the lesion site limits the loss of functions in spinal cord injuries. The refinement of an innovative array then allows both a more efficient and independent epidural stimulation along multiple segments, and simultaneous multisite recordings from the spinal surface.
The topic of this research project is very timely, with many clinical and experimental evidence recently published in prestigious scientific journals and in the media. The pioneeristic vision of this study considers chronic spinal lesions as a disturbance that can be treated to regain volitional motor control.
The important results collected can strongly improve functional recovery after spinal cord injury and potentially also in the presence of other neuromotor disturbances. These preclinical results provide strong fundamentals for potential future translations of technology and protocols to improve current clinical neuromodulation and will potentially lead to the patenting of a new array and electrical stimulation protocol. This study might also sustain the introduction of a novel generation of epidural electrostimulators to improve the recovery of functions after injury.
Considering the high incidence of spinal cord injuries, the outcomes of this research might contribute to reducing the overall financial costs related to the health care and welfare of persons with a spinal cord injury, improving their quality of life and in turn increasing their productivity and participation to society. Indeed, the unique features of DS technology would allow a groundbreaking and highly efficient neurorehabilitation to be accessible to a greater population of persons living with a spinal cord injury and likely with other neurodegenerative disturbances of the neuromotor system. Moreover, improvements on the multielectrode array will advance research, industry and clinics and, along with DS, can represent a valuable European asset and reference for neurorehabilitation.
Finally, the new laboratory recently created within the International School for Advanced Studies is a research infrastructure to be nourished and soon name among the most productive European groups in the field.
New cortical and spinal epidural arrays with independent electrodes for motor facilitation with DS